Georg Matheis

Avoiding reperfusion injury after limb revascularization: Experimental observations and recommendations for clinical application

This study tests the hypothesis that reperfusion injury is the principal cause of limb loss after acute arterial occlusion and that this injury is avoidable. Of 61 isolated hindlimbs amputated at the level of the hip joint, 17 were controls (group I), 5 were perfused without ischemia to establish the validity of the model (group II), and 15 underwent 4 hours of ischemia at room temperature without reperfusion (group III). Acute embolectomy was simulated in 24 limbs after 4 hours of ischemia; 12 were reperfused with standard Krebs-Henseleit solution at 100 mm Hg (group IV), and 12 were reperfused under controlled conditions (i.e., 37 degrees C, 50 mm Hg) with substrate-enriched modified reperfusate (group V). Leg volume, water content, contractile function, and high-energy phosphate content were assessed and data were expressed as mean +/- SD. Four hours of ischemia caused a profound fall in adenosine triphosphate content (4.0 vs 26.0 mmol/L/gm of protein, p less than or equal to 0.001). Uncontrolled reperfusion resulted in severe reperfusion injury; massive edema developed (83% vs 75%, p less than or equal to 0.01), leg volume increased markedly (21.5% above control, p less than or equal to 0.001), and no contractile function followed electrical stimulation. In contrast, controlled reperfusion resulted in normal water content (76.9% vs 75.0%, NS) and minimal change of leg volume (5.5% +/- 5% of control, NS), replenished adenosine triphosphate completely (24.2 vs 26.4 mmol/L/gm of protein, NS), and restored immediate contractile function in all limbs (24.3% +/- 14% of control). This study shows that 4 hours of room-temperature ischemia (18 degrees C) does not produce irreversible damage of the rat hindlimb because the reperfusion injury that follows uncontrolled reperfusion can be avoided. Immediate recovery of contractile function can be restored if the conditions of reperfusion are controlled by gentle reperfusion pressure (50 mm Hg) at 37 degrees C and if a modified substrate-enriched, hyperosmotic, alkalotic, low-Ca++ reperfusate is administered.

Circulating endothelin in patients undergoing coronary artery bypass grafting

Increased synthesis of endothelin, (a powerful physiological vasoconstrictor), is a uniform response to endothelial injury and has been associated with myocardial ischemia and reperfusion. This study tests the hypothesis that coronary artery bypass grafting (CABG) affects endothelin plasma concentrations in various vascular beds. Twenty-four CABG patients were included in this study. Endothelin was determined in multiple plasma specimens obtained from superior vena cava, aortic root and coronary sinus (CS). Venous endothelin plasma concentrations collected in CABG patients before surgery were 1.16 +/- 0.18 pg/ml. They increased after sternotomy (1.71 +/- 0.12 pg/ml) and during (2.97 +/- 0.27 pg/ml) and after cardiopulmonary bypass (CPB, 2.72 +/- 0.21 pg/ml). There is no net release of endothelin from the coronary circulation before (aorta 2.26 +/- 0.13 pg/ml vs CS 2.44 +/- 0.17 pg/ml, not significant (n.s.), during (cardioplegia 2.55 +/- 0.17 pg/ml vs CS 2.45 +/- 0.15 pg/ml, n.s.), and after aortic cross-clamping (aorta 2.95 +/- 0.23 pg/ml vs coronary sinus 2.71 +/- 0.18 pg/ml, n.s.). Pulmonary endothelin clearance is preserved on partial bypass (aorta 2.26 +/- 0.13 pg/ml vs vena cava 2.86 +/- 0.18 pg/ml, P < 0.003), but remains inhibited even 10-30 min after release of the aortic cross-clamp (aorta 2.95 +/- 0.23 pg/ml vs vena cava 2.97 +/- 0.27 pg/ml, n.s.). Two out of 24 patients had severe myocardial ischemia. These patients showed particularly high endothelin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukocyte filtration fails to limit functional neutrophil activity during cardiac surgery

Abstract. Objective and design: The beneficial effects of leukocyte filtration on the outcome of cardiac surgery with cardiopulmonary bypass (CPB) is probably due to the limitation of pathogenesis mediated by over-stimulated neutrophils. However, the influence of leukocyte filtration on the functional neutrophil activity has not been studied in detail. Therefore, by using different filtration timing strategies we determined neutrophil effector functions before and after the filter passage as well as blood surrogate markers for neutrophil activation.¶Methods: We randomly assigned 80 cardiac surgery patients to four groups (n = 20 each) without (I) and with three different filtration timing strategies (II–IV). As functional end points neutrophil phagocytic activity and oxidative burst upon ex vivo stimulation with E.coli were analyzed from blood of 31 patients whereas polymorphonuclear elastase (PMNE), myeloperoxidase, and malondialdehyde (MDA), a marker for lipid peroxidation was determined in plasma samples from 80 patients. Blood was harvested immediately before and behind the filter (Pall LG6) at different times during CPB.¶Results: We found that none of the filtration strategies either reduced the number of neutrophils capable of eliciting phagocytic activity and oxidative burst or the activity per cell. In contrast, PMNE and MPO levels in peripheral venous blood were found to be significantly increased in groups II–IV compared with group I throughout the entire filtration period in all patients. MDA was not enhanced in the filter groups.¶Conclusions: Our results show that the leukocyte depletion filter in the arterial line of the heart-lung machine failed to limit neutrophil stimulation but rather augmented PMNE plasma levels. We speculate that augmented PMNE and MPO levels mainly stem from neutrophils that are captured within the mesh of the leukocyte filter.

Effect of internal thoracic artery preparation on blood loss, lung function, and pain

BACKGROUND Postoperative blood loss, respiratory distress, and pain after coronary artery operation were assessed in a prospective, randomized, clinical study comparing two techniques of internal thoracic artery preparation. METHODS In group A (n = 57) the internal thoracic artery was dissected with the entire surrounding connective tissue after opening the pleura, using routine lateral pleural drainage. In group B (n = 55) a venoarterial pedicle was prepared without surrounding muscle leaving the pleura intact. We assessed blood loss, clinical outcome, lung function, location, intensity, and quality of pain 6 days and 3 months after the operation. RESULTS Significantly higher blood loss was observed in group A (A, 608+/-58 mL; B, 470+/-48 mL; p = 0.027). Forced expiratory volume in 1 second was significantly decreased in group A 6 days after surgery (A, 76.0%+/-1.6%; B, 83.2%+/-1.6%; p = 0.020). The forced expiratory volume in 1 second correlated to inspiratory vital capacity, which confirmed the advantage of the venoarterial technique (A, 0.771+/-0.021; B, 0.832+/-0.020; p = 0.003). Vital capacity was significantly higher in the venoarterial group at 3 months (A, 85.2%+/-2.1%; B, 98.5%+/-1.2%; p = 0.009), but not on postoperative day 6. The incidence of pleural effusion and atelectasis was significantly higher in group A (effusion: A, 52.6%; B, 23.6%; p = 0.002; atelectasis: A, 42.1%; B, 20.0%, p = 0.015). Sternal pain (A, 36.8%; B, 9.1%; p = 0.001) and suspenders pain (A, 33.3%; B, 7.3%; p = 0.001) occurred more often in group A. When using a multidimensional pain score, patients in group A experienced significantly sharper (6 days: A, 6.7+/-0.3; B, 3.3+/-0.2; p = 0.018; 3 months: A, 3.5+/-0.3; B, 1.4+/-0.3; p = 0.046) and more annoying pain (6 days: A, 7.6+/-0.2; B, 2.7+/-0.1; p = 0.036; 3 months: A, 6.6+/-0.3; B, 2.3+/-0.2; p = 0.040). CONCLUSIONS These results demonstrate that the venoarterial preparation technique is superior to conventional internal thoracic artery preparation regarding postoperative blood loss, lung function, and pain.

Hemodynamics and gas exchange during carbon dioxide insufflation for totally endoscopic coronary artery bypass grafting

BACKGROUND In addition to single-lung ventilation (SLV), positive-pressure CO2 insufflation is mandatory for totally endoscopic coronary artery bypass grafting. Studies on the effects of unilateral CO2 insufflation on hemodynamics produced controversial results, and bilateral insufflation has not been studied to our knowledge. The present study sought to investigate hemodynamics and gas exchange during unilateral and bilateral CO2 insufflation in patients who underwent totally endoscopic coronary artery bypass grafting. METHODS Eleven hemodynamic and gas exchange variables were monitored during 22 totally endoscopic coronary artery bypass grafting procedures with unilateral (n = 17) or bilateral (n = 5) CO2 insufflation at a pressure of 10 to 12 mm Hg. Data were obtained at baseline with double-lung ventilation, after institution of SLV, during insufflation, after cardiopulmonary bypass during SLV, and after return to double-lung ventilation. RESULTS Arterial oxygen tension decreased significantly during SLV, whereas the peak inspiratory pressure increased. In addition, central venous pressure and heart rate increased significantly during insufflation, but mean arterial pressure remained unchanged. Although the end-tidal CO2 pressure did not change, arterial carbon dioxide tension increased progressively to a maximum of 44.6 +/- 5.9 mm Hg during unilateral insufflation, and 55.7 +/- 14.6 mm Hg during bilateral insufflation (p < 0.05 versus baseline and between groups). Mixed venous oxygen saturation declined during SLV regardless of CO2 insufflation and recovered to baseline once double-lung ventilation was restarted. Left and right ventricular ejection fractions remained unaltered. No patient required inotropic or vasopressor support. CONCLUSIONS Carbon dioxide insufflation for totally endoscopic coronary artery bypass grafting with SLV had no adverse effects on hemodynamics. In contrast to a moderate increase of arterial carbon dioxide tension during unilateral insufflation, markedly elevated arterial carbon dioxide tension levels remain a cause of concern during bilateral insufflation.

Studies of hypoxemic/reoxygenation injury: Without aortic clamping:: V. Role of the l-arginine–nitric oxide pathway: The nitric oxide paradox

This study tests the hypothesis that nitric oxide, which is endothelial-derived relaxing factor, produces reoxygenation injury via the L-arginine-nitric oxide pathway in hypoxemic immature hearts when they are placed on cardiopulmonary bypass. Twenty 3-week-old piglets undergoing 2 hours of hypoxemia (oxygen tension about 25 mm Hg) on a ventilator were reoxygenated by initiating cardiopulmonary bypass (oxygen tension about 400 mm Hg). Five animals were not treated, whereas the pump circuit was primed with the nitric oxide-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 4 mg/kg) in five piglets. L-Arginine, the substrate for nitric oxide, was administered in a fivefold excess (20 mg/kg), together with L-NAME in five piglets (L-NAME and L-arginine), and given alone in five other piglets (L-arginine). Five normoxemic, instrumented piglets served as a control group, and five others underwent 30 minutes of cardiopulmonary bypass without preceding hypoxemia. Left ventricular contractility was determined as end-systolic elastance by pressure-dimension loops. Myocardial conjugated dienes were measured as a marker of lipid peroxidation, and the antioxidant reserve capacity (malondialdehyde production in tissue incubated with t-butylhydroperoxide) was measured. Nitric oxide level was determined in coronary sinus plasma as its spontaneous oxidation product, nitrite. Cardiopulmonary bypass per se did not alter left ventricular contractility, cause lipid peroxidation, or lower antioxidant capacity. Reoxygenation without treatment depressed cardiac contractility (end-systolic elastance 38% +/- 12% of control*), raised nitric oxide (127% above hypoxemic values), increased conjugated dienes (1.3 +/- 0.2 vs 0.7 +/- 0.1, control*), and reduced antioxidant reserve capacity (910 +/- 59 vs 471 +/- 30, control*). Inhibition of nitric oxide production by L-NAME improved end-systolic elastance to 84% +/- 12%,** limited conjugated diene elution (0.8 +/- 0.1 vs 1.3 +/- 0.2, no treatment**), and improved antioxidant reserve capacity (679 +/- 69 vs 910 +/- 59, no treatment**). Conversely, L-arginine counteracted these beneficial effects of L-NAME, because left ventricular function recovered only 24% +/- 6%,* conjugated dienes were 1.2 +/- 0.1,* and antioxidant reserve capacity was 826 +/- 70.* L-Arginine alone caused the same deleterious biochemical changes as L-NAME/L-arginine and resulted in 60% mortality. The close relationship between postbypass left ventricular dysfunction (percent end-systolic elastance) and myocardial conjugated diene production (r = 0.752) provides in vivo evidence that lipid peroxidation contributes to myocardial dysfunction after reoxygenation.(ABSTRACT TRUNCATED AT 400 WORDS)

Occupational exposure to inhalational anesthetics during cardiac surgery on cardiopulmonary bypass

BACKGROUND Eventual hazards from occupational exposure of operating room personnel to inhalational anesthetic agents cannot yet be definitively excluded. We determined if occupational exposure of operating room personnel to waste anesthetic gases during cardiopulmonary bypass (CPB) complies with the established governmental limits. METHODS Ten adults underwent inhalational anesthesia for coronary artery bypass grafting with nitrous oxide and either sevoflurane (n = 5) or desflurane (n = 5). The administration of inhalational anesthetic agents was stopped before initiation of CPB. Gas samples were obtained before and during CPB every 90 seconds from the breathing zones of anesthesiologist (A), surgeon (S), and perfusionist (P). Time-weighted averages (TWA) over the time of exposure were calculated. RESULTS The surgeons exposure to nitrous oxide was 9.3 +/- 1.9 parts per million (ppm) before and 3.0 +/- 1.4 ppm during CPB (A: 6.7 +/- 1.1 ppm and 0.5 +/- 0.1 ppm; P: 3.7 +/- 1.4 ppm during CPB). Occupational exposure to desflurane was 0.21 +/- 0.10 ppm before and 0.62 +/- 0.28 ppm during CPB for the surgeon (A: 0.02 +/- 0.01 ppm and 0.02 +/- 0.003 ppm; P: 0.82 +/- 0.26 ppm during CPB), thereby exceeding the given limit of 0.5 ppm. Exposure levels of sevoflurane were below the 0.5 ppm limit at all times, as were nitrous oxide levels (threshold limit: 25 ppm). CONCLUSIONS Although occupational exposure to inhalational anesthetic agents was low at most times during the study and none of the operating room staff complained about subjective or objective impairment or discomfort, all measures must be taken to further minimize occupational exposure, including sufficient air conditioning and routine use of waste gas scavenging systems on CPB equipment.

Correction of simple congenital heart defects in infants and children through a minithoracotomy

BACKGROUND Minimally invasive surgical techniques in pediatric cardiac surgery have evolved throughout the last 10 years. Advantages of minimally invasive procedures include excellent cosmetic results and superior postoperative outcome. However, safety of minimally invasive techniques has to be proven. METHODS In 21 female infants and children, a right anterolateral thoracotomy was performed. Mean age was 7.1 years (0.5 to 16.6 years) and mean body weight was 20.8 kg (8.3 to 56 kg). The following defects were repaired: atrial septum defect type II (n = 14); partial atrioventricular septum defect (n = 3); partial anomalous pulmonary venous connection (n = 2); ventricular septum defect (n = 2); mitral valve insufficiency (n = 1); and resection of an embolized atrial septum defect occluder (n = 1). In two cases, aortic cross-clamping was performed by using a transthoracic clamp. In 5 patients, femoral cannulation was performed. Skin incisions were limited to 4 to 7 cm. RESULTS There was no operative or late mortality. Mean operation time, bypass time, and aortic cross-clamp time were 138 (95 to 275), 72 (32 to 179), and 35 (12 to 120) minutes, respectively. Mean postoperative mechanical ventilation time, mean intensive care unit stay, and mean hospital stay were 3.9 hours (1 to 12 hours), 1.4 days (1 to 3 days), and 12 days (8 to 18 days), respectively. Postoperative complications included hemorrhage in 1 patient requiring surgical intervention. Mean follow-up period was 13.3 months (1 to 36 months). All patients were in New York Heart Association class I postoperatively. Trivial mitral insufficiency was evident in 1 patient operated for partial atrioventricular septum defect. CONCLUSIONS A small right anterolateral thoracotomy as a minimally invasive technique in pediatric cardiac surgery is a safe and suitable alternative in the operative management of simple congenital heart defects. Cosmetic results are superior, however, improved postoperative outcome has to be proven.

Synthetic protein treated versus heparin coated cardiopulmonary bypass surfaces: similar clinical results and minor biochemical differences

OBJECTIVE Complications associated with cardiopulmonary bypass (CPB) have gained more attention due to increased interest in coronary artery bypass grafting without CPB. The impact of heparin coating of CPB circuits has been discussed controversially. The present study examines if the treatment of the oxygenator surface with a synthetic protein may serve as an alternative to a completely heparin coated circuit. METHODS Fifty-eight patients undergoing coronary artery bypass grafting with CPB were randomly assigned to completely heparin coated circuits or synthetic protein treated oxygenators in a double blind protocol, focussing on the inflammatory reaction resulting in membrane damage, coagulation changes and markers of cerebral injury or dysfunction. Treatment groups did not differ as to preoperative demographics, and intraoperative clinical data. Patients with any neurologic disease or risk factors for cerebral dysfunction were not included in the study. RESULTS Postoperative clinical data did not differ between groups. Both surface treatments resulted in similar coagulation activation, hyperfibrinolysis and disseminated intravascular coagulation. Platelet count displayed a difference in favour of the heparin coated group (P = 0.029). Increased leukocyte activation reflected by rising myeloperoxidase concentrations on CPB was present in both synthetic protein and heparin coating groups. Interleukins 6 and 8 reacted similarly, but interleukin 8 increased significantly more (P = 0.0061) at the end of surgery in patients treated with protein treated oxygenators. The same pattern was observed for complement activation as determined by total complement complex (P = 0.006). Both surface changes resulted in moderately increased S-100B protein and neuron specific enolase, without difference between groups. Both markers did not reach concentrations associated with clinical manifestation of cerebral injury. CONCLUSIONS These results in routine patients with short bypass time, imply that protein treated oxygenators are associated with a limited increase of biochemical markers similar to heparin coating. However, significantly lower interleukin 8 release and complement activation can be achieved by heparin coating. The protein treatment is a standard feature of the oxygenator examined in both groups. It is not associated with additional cost and therefore appropriate for use in routine patients.

Timing of leukocyte filtration during cardiopulmonary bypass

The effects of leukocyte filtration on the outcome of cardiac surgery with cardiopulmonary bypass (CPB) have been shown by numerous investigators. In the majority of cases a leukocyte filter is placed in the arterial line instead of a standard arterial line filter and used throughout CPB. However, protocols to optimize onset and duration of leukocyte filtration have not been sufficiently evaluated to date. In this paper, current efforts to improve such protocols are demonstrated and discussed. These efforts are based on studies of leukocyte pathogenicity during cardiac surgery. A first study (double-blind randomized) was performed in routine coronary artery bypass graft (CABG) patients to evaluate whether short-term leukocyte filtration during reperfusion by release of the aortic crossclamp would reduce reperfusion-associated myocardial damage. Further data compare the efficacy of three different filtration concepts to reduce CPB-and/or reperfusion-associated leukocyte pathogenicity. Clinical endpoints, standard laboratory variables and functional in vitro assays are provided and discussed.